Zonisamide is currently available as an anti-epileptic agent which possesses anti-convulsant and anti-neurotoxic effects. Zonisamide is also known as 1,2-benzisoxazole-3-methane sulfonamide or 3-(sulfamoylmethyl)-1,2-benzisoxazole. It has the following chemical formula: 
Japanese Patent 53-77057 and U.S. Pat. No. 4,172,896 describe the preparation of BOS—Cl, an intermediate in zonisamide synthesis. According to these patents, the synthesis of BOS—Cl is performed by refluxing sodium 1,2-benzisoxazole-3-methanesulfonate in POCl3.
In general, acyl-halides and sulfonyl-halides are prepared by the reaction of the corresponding carboxylic acids or sulfonic acids with POCl3, PCl5 or SOCl2. In the case of sulfonic acid sodium salts, thionyl-chloride is less reactive and the reaction requires a catalyst. In general, the conversion of sulfonyl-chloride to the corresponding sulfonyl-amide is performed with ammonia in aqueous solution or with ammonia gas.
The method of zonisamide preparation, as described in Japanese Patent 53-77057 and U.S. Pat. No. 4,172,896, uses ammonia gas to amidate the BOS—Cl in ethylacetate. An alternative method is to use aqueous ammonia. This amidation reaction is exemplified in the preparation of a zonisamide derivative having one fluorine atom in the aromatic ring.
The use of POCl3 as a reagent for chlorination presents some problems for industry and poses significant health hazards. For example, POCl3 is a nerve gas precursor and exposure to its vapor may result in chemical pneumonitis and pulmonary edema.
There is thus a continuing need to improve the preparation of BOS—Cl and the conversion of BOS—Cl to zonisamide.